Trial of Romidepsin and Bortezomib for Multiple Myeloma

(There was a change in the Sponsor's research strategy; safety concerns were not a factor.)

Sponsor:

Celgene Corporation

ClinicalTrials.gov Identifier:

NCT00765102

First Posted: October 2, 2008

Last Update Posted: May 4, 2016

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This is a phase II, open-label, multicenter, dual-strata study designed to evaluate the efficacy and safety of IV romidepsin given in combination with IV bortezomib for multiple myeloma (MM) patients with refractory or relapsed disease. Patients will be enrolled into one of two strata, bortezomib-resistant or bortezomib non-resistant.

Disease progression for participants relapsing from a complete response: reappearance of serum or urinary paraprotein on imunofixation, >= 5% plasma cells in the bone marrow aspirate or biopsy, increase in existing lytic bone lesions or soft tissue plasmacytomas or new bone lesions or soft tissue plasmacytomas, development of hypercalcemia.

Kaplan Meier Estimate for Time to Response Assessed by the Investigator [ Time Frame: up to month 8 ]

The time to the first response is defined as the time from the initiation of therapy to the first evidence of a confirmed response (complete response, very good partial response, partial response or minimal response).

Complete Response: disappearance of monoclonal protein from blood and urine, and disappearance of soft tissue plasmacytomas, <5% plasmas cells in marrow and no increase of lytic bone lesions.

Very Good Partial Response: disappearance of plasmacytomas, no increase of lytic bone lesions, serum and urine M-protein not detectable by immunofixation, other.

Disease progression for participants relapsing from a complete response: reappearance of serum or urinary paraprotein on imunofixation, >= 5% plasma cells in the bone marrow aspirate or biopsy, increase in existing lytic bone lesions or soft tissue plasmacytomas or new bone lesions or soft tissue plasmacytomas, development of hypercalcemia.

Kaplan Meier Estimates for Progression-free Survival Assessed by the Investigator [ Time Frame: up to month 8 ]

Progression-free survival is the time from initiation of therapy to progressive disease, removal from study for any reason, death from any cause, or the last follow-up visit, whichever occurs first.

Disease progression for participants relapsing from a complete response: reappearance of serum or urinary paraprotein on imunofixation, >= 5% plasma cells in the bone marrow aspirate or biopsy, increase in existing lytic bone lesions or soft tissue plasmacytomas or new bone lesions or soft tissue plasmacytomas, development of hypercalcemia.

Romidepsin was given as an infusion on Days 1, 8 and 15 of each 28-day cycle. Bortezomib was administered twice a week for two consecutive weeks (Days 1, 4, 8 and 11) followed by a 17-day rest period.

Patients were treated to a maximum response plus two additional cycles or a maximum of eight cycles.

Drug: Bortezomib

Bortezomib was administered at a dose of 1.0 mg/m^2 as an intravenous (IV) push over 3 to 5 seconds twice weekly for 2 consecutive weeks (Days 1, 4, 8 and 11) of each 28-day cycle. On days that bortezomib and romidepsin were administered together, bortezomib was administered prior to the romidepsin infusion.

Patients were treated to a maximum response plus two additional cycles or a maximum of eight cycles.

Other Name: VELCADE®

Drug: Romidepsin

Romidepsin initially was administered at a dose of 10 mg/m^2 as a 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of each 28-day cycle. Based on the occurrence of Grade 3 thrombocytopenia at this dose level, the dose was reduced by protocol amendment to 8 mg/m^2.

Other Names:

ISTODAX®

depsipeptide

FK228

Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:

18 Years and older (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria

Patients must fulfill all of the following criteria to be eligible for study participation:

Male or female patients aged ≥ 18 years old

Has given voluntary written informed consent before any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care

Previously diagnosed with multiple myeloma (MM) based on standard criteria as follows:

All women of childbearing potential must use an effective barrier method of contraception. Male patients should use a barrier method of contraception during the treatment period and for 3 months thereafter

Patients must meet the following laboratory criteria at Baseline (Day 1 of Cycle 1, before study drug administration):

Platelet count ≥ 100*10^9/L

Absolute neutrophil count ≥ 1.5*10^9/L

OR if the bone marrow is extensively infiltrated

Platelet count ≥ 75*10^9/L

Absolute neutrophil count ≥ 1.0*10^9/L

Patients must meet the following laboratory criteria at the Screening visit conducted within 14 days of enrollment (Day 1, Cycle 1):

Calculated or measured creatinine clearance: ≥30 mL/minute. Patient with a creatinine >10mL/min and <30 mL/min due to significant myelomatous involvement of the kidneys may be enrolled in the study after receipt of approval from the lead investigator and sponsor

Serum potassium ≥ 3.8 mmol/L

Serum magnesium >1.8 mg/dL

Serum phosphorus ≥ lower limit of normal (LLN)

Exclusion Criteria

Patients are ineligible for entry if any of the following criteria are met:

Chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) or thalidomide, lenalidomide, arsenic trioxide, bortezomib, or glucocorticosteroids within 3 weeks prior to the first dose of romidepsin

Prior major surgery within 3 weeks prior to the first day of treatment

Use of any investigational agent within 4 weeks of study entry

Prior therapy with romidepsin

Any known cardiac abnormalities such as:

Congenital long QT syndrome;

QTc interval ≥ 500 milliseconds;

Myocardial infarction within 6 months of Day 1. Subjects with a history of myocardial infarction between 6 and 12 months prior to the first day of cycle one who are asymptomatic and have had a negative cardiac risk assessment (treadmill stress test, nuclear medicine stress test, or stress echocardiogram) since the event may participate;

Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV In any patient in whom there is doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present;

An ECG recorded at screening showing evidence of cardiac ischemia (ST depression depression of ≥2 mm, measured from isoelectric line to the ST segment). If in any doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present;

A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD);

Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other causes;

Uncontrolled hypertension, i.e., blood pressure (BP) of ≥160/95; patients who have a history of hypertension controlled by medication must be on a stable dose (for at least one month) and meet all other inclusion criteria; or